There is an urgent clinical need for the development of opioid analgesics with novel biological activity profiles that lack the limiting side effects of the currently available opiates. It has been shown that the propensity of [unreadable] opioid agonists to produce analgesic tolerance and physical dependence can be reduced by co-administration of a d opioid antagonist, a cannabinoid (CB1) antagonist, a substance P (NK1) antagonist or an opioid receptor like (ORL1) antagonist. On the basis of this evidence we propose to develop systemically active, bifunctional compounds with a mixed [unreadable] opioid agonist/d opioid antagonist-, [unreadable] agonist/CB1 antagonist-, [unreadable] agonist/NK1 antagonist- or [unreadable] agoist/ORL1 antagonist profile as analgesics expected to produce little or no tolerance and physical, dependence, and with low addiction liability. Bifunctional ligands with these profiles that are systemically active and able to cross the blood-brain barrier (BBB) have not been reported to date. The design of the bifunctional ligands will be based on attachment of the various antagonist pharmacophores (peptides and non-peptides) to various sites of the potent and highly selective [unreadable] opioid agonist peptide [Dmt1]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2;Dmt = 2'6'- dimethyltyrosine) either directly or via a short linker in a way that does not interfere with the agonist/antagonist properties of the two components. This will be done by careful consideration of known structure-activity relationships (SAR) of the two components in conjunction with molecular modeling of ligand docking to the receptor binding sites. [Dmt1]DALDA was chosen as the [unreadable] agonist component because of its high analgesic potency, oral bioavailability, high stability, long elimination half-life and long duration of action. There is evidence to indicate that the proposed [Dmt1]DALDA-antagonist conjugates will be able to penetrate into the central nervous system because the [Dmt1]DALDA component will confer blood-brain barrier crossing ability upon the entire bifunctional construct. This has been shown to be the case with two already prepared [unreadable] opioid agonist/d antagonists of this type which produced potent centrally mediated antinociception when given subcutaneously (s.c.). The bifunctional ligands will be prepared by solid-phase synthesis or by a combination of solid-phase- and solution peptide synthesis techniques. The in vitro biological profiles of the compounds will be determined by performing receptor binding assays, isolated tissue assays and [35S]GTP?S binding assays using HEK cells containing singly expressed [unreadable] opioid, d opioid, CB1, NK1, or ORL1 receptors. Their analgesic potencies will be determined in acute pain models (tail-flick and hot plate) and in the chronic constriction injury model as a model of neuropathic pain. Furthermore, the propensities of the compounds to produce analgesic tolerance, physical dependence, addiction (place conditioning paradigm), constipation and respiratory depression will be examined.